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EC number: 800-172-4
CAS number: 398141-87-2
OF DOSING FORMULATIONS
analysed dosing formulations contained 89.7% to 112% of the test
substance which was within the Charles River SOP range of target
concentrations for suspensions (85% to 115%), and were homogeneous.
- The test substance was not
detected in the analysed vehicle formulation that was administered to
the control group (Group 1).
- Results of homogeneity and
concentration analyses are attached.
The objectives of this study were to
evaluate the potential toxicity of the test item when administered daily
by oral gavage to Sprague Dawley rats for a minimum of 90 consecutive
days, as well as to evaluate the recovery, persistence, or progression
of any effects following a minimum of a 28-day recovery period. The
protocol was designed in general accordance with OECD Guideline for the
testing of Chemicals 408 (September 1998).
Test item in the vehicle (corn oil)
was administered orally by gavage once daily for a minimum of 90
consecutive days to 5 toxicology groups (Groups 2, 3, 4, 5, and 6) of
Crl:CD(SD) rats. Dosage levels were 5, 25, 125, 250, and 500 mg/kg/day
for Groups 2, 3, 4, 5, and 6, respectively. A concurrent control group
(Group 1) received the vehicle on a comparable regimen. The dose volume
was 5 mL/kg for all groups. Groups 1 and 6 each consisted of 15
animals/sex and Groups 2–5 each consisted of 10 animals/sex. Following a
minimum of 90 consecutive days of dose administration, 9–10
animals/sex/group were euthanised; the remaining 5 animals/sex in the
control and high-dose groups were euthanised following a 28/29-day
nondosing (recovery) period. All animals were observed twice daily for
mortality and moribundity. Clinical examinations were performed daily,
and detailed physical examinations were performed weekly (± 2 days).
Individual body weights and cage food weights were recorded weekly (± 2
days). Functional observational battery (FOB) and motor activity data
were recorded for all animals during Study Week 12. Ophthalmic
examinations were performed during Study Weeks -2 and 12. Clinical
pathology parameters (haematology, coagulation, serum chemistry, and
urinalysis) were analysed for all animals assigned to the primary (Study
Week 12/13) and recovery (Study Week 16/17) necropsies. Complete
necropsies were conducted on all animals, and selected organs were
weighed at the scheduled necropsies. Selected tissues were examined
microscopically from all animals.
One female (No. 8487) in the 25
mg/kg/day group was found dead prior to dosing on Study Day 82. This
animal was noted with a ruptured mass at the gross necropsy examination
and was considered to be the likely cause of death.
One male (No. 8381) in the 125
mg/kg/day group was found dead prior to dosing on Study Day 88. There
were no clinical observations noted and no macroscopic findings noted at
the gross necropsy. The cause of death was undetermined.
All other animals survived to the
scheduled necropsy. There were no test substance-related effects on
haematology, serum chemistry, urinalysis, functional observational
battery parameters, or motor activity. There were no test
substance-related ophthalmic or macroscopic findings. Higher prothrombin
time and activated partial thromboplastin time noted in the 500
mg/kg/day group males at Study Week 12/13 were considered to be
potentially related to test material administration.
Test substance-related clinical
observations noted in the 250 and 500 mg/kg group males and/or females
were clear and/or yellow material around the mouth. Salivation, yellow
material around the mouth, and yellow material around the urogenital
and/or anogenital areas were noted in the 250 mg/kg/day group females
and/or the 500 mg/kg/day group males and/or females. In addition, clear
material around the mouth was noted in the 125 mg/kg/day group males.
There were no clinical observations noted during the recovery period.
Test substance-related, nonadverse
higher body weights and correlating higher food consumption were noted
for the 250 and 500 mg/kg/day group females throughout the dosing
period. The effects on body weights and food consumption did not persist
during the recovery period for the 250 mg/kg/day group females. Test
substance-related higher food consumption persisted during the recovery
period for the 500 mg/kg/day group females.
Test substance-related changes in
organ weights were noted in the 125, 250, and/or 500 mg/kg/day group
males and females at the primary necropsy. Higher kidney weights were
noted in the 125 mg/kg/day group males and the 250 and 500 mg/kg/day
group males and females. There were no microscopic correlates or a
definitive dose-response noted. Higher mean liver weights were noted in
the 125 mg/kg/day group females and the 250 and 500 mg/kg/day group
males and females. Higher weights correlated microscopically with
hepatocellular hypertrophy and were considered to be an adaptive
response to test item administration. Higher mean thyroid/parathyroid
gland weights were noted in the 500 mg/kg/day group males and females,
correlated with follicular cell hypertrophy, and were considered to be
an adaptive response. At the recovery necropsy, higher mean kidney,
liver, and thyroid/parathyroid gland weights persisted in the 500
mg/kg/day group females, with no microscopic correlates. Kidney, liver,
and thyroid/parathyroid gland weights in the 500 mg/kg/day group males
were similar to the control group, consistent with recovery.
At the primary necropsy, test
item-related microscopic findings noted in the kidneys of the 125, 250,
and/or 500 mg/kg/day group males consisted of increased alpha-2u
globulin-immunopositive hyaline droplet accumulation, single cell
necrosis within proximal convoluted tubule (PCT) epithelial cells,
granular casts, and a higher incidence and/or severity of chronic
progressive nephropathy (CPN); hyaline droplet accumulation was
additionally noted in the 5 and 25 mg/kg/day group males. Hepatocellular
hypertrophy was noted in the liver of the 125 mg/kg/day females and the
250 and 500 mg/kg/day group males and females and correlated with higher
liver weights. Thyroid follicular cell hypertrophy was noted in the 500
mg/kg/day group males and females and correlated with higher
thyroid/parathyroid gland weights. At recovery, renal findings noted in
the 500 mg/kg/day group males consisted of increased alpha-2u globulin
immunopositivity, granular casts, and higher incidence/severity of CPN.
Hepatocellular and thyroid follicular cell hypertrophy were not noted in
the 500 mg/kg/day group males and females at the recovery necropsy.
Based on the results of this study,
oral administration of test item to Crl:CD(SD) rats at dosage levels of
5, 25, 125, 250, and 500 mg/kg/day for a minimum of 90 days was
generally well tolerated at all dosages. Adverse microscopic renal
changes related to a well-known male rat-specific alpha-2u globulin
accumulation were noted in male rats at ≥ 125 mg/kg/day. All other
findings were considered to be nonadverse. Therefore, the
no-observed-adverse-effect level (NOAEL) was considered to be 25
mg/kg/day for male rats and 500 mg/kg/day for female rats tested in this
study. However, because the renal changes observed in the male rats in
this study were in association with alpha-2u globulin accumulation,
which is a well-known male rat-specific effect, not occurring in female
rats or other species, including humans, and thus are of no human
relevance, this effect should be excluded from any subsequent human risk
assessment. Thus, in the absence of the alpha 2u globulin accumulation
effect, the NOAEL relevant for human risk assessment is considered to be
500 mg/kg/day, the highest dosage level tested for both sexes of rats in
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